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A Promising Target for Improving Breast Cancer Outcomes with Immunotherapy

In a recent publication in the journal Immunity, researchers at the Rosalind and Morris Goodman Cancer Institute (GCI) discovered a new target for improving breast cancer response to immunotherapy. The study was co-led by M.D/PhD. candidate Tarek Taifour, and recent GCI graduate Sherif Attalla, PhD, under the supervision of Prof. William Muller. Their findings addressed the critical challenge of treatment resistance in the field of immunotherapy.

Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by aggressiveness and higher risks of recurrence. Immunotherapies, drugs which prime a patient’s immune system to fight cancer, are sometimes used to treat TNBC patients. Tarek discussed with us the relevance of immunotherapy for TNBC patients, noting, "Immunotherapies have shifted the paradigm for cancer treatment, but response rates in Triple Negative Breast Cancers remain low. One cause for this is T cell stromal restriction, a phenomenon where T cells are excluded to the stroma and unable to infiltrate the tumor epithelial areas.” T cells are a type of immune cell which have the potential to kill cancer. The stroma refers to the area of non-cancer cells within and around a tumor – when T cells are sequestered in this area, they are not able to contact the cancer cells to kill them. This phenomenon presents a significant challenge in the field of immunotherapy and is often a cause of patients not being able to benefit from these treatments.

To address this problem, the researchers investigated models of breast tumors with low levels of permeating immune cells. Tarek elaborated on their findings, stating, “In this paper, we found that the secreted protein Chitinase-3 like 1 (Chi3l1) plays a prominent role in T cell stromal restriction in TNBCs and other cancers. In particular, Chi3l1 recruits neutrophils which block T cell entry into the tumor.” Neutrophils are another type of immune cell which can be stimulated to create dense, web like structures to trap other cells. This is beneficial when neutrophils are recruited to trap infecting bacteria or other microbes, but when hijacked by cancer these web-structures block the cancer-killing T cells from entering the tumor. “Targeting Chi3l1 increases T cell infiltration which delays breast cancer progression and improves response to immunotherapy. Our findings demonstrate that targeting Chi3l1 is a promising therapeutic strategy to promote anti-tumor immunity and improve response to immunotherapy," highlighted Tarek about the implications of their discovery. They hope that targeting Chi3l1 in combination with immunotherapies will increase the benefit of these drugs for TNBC patients, as well as patients with other types of cancer.

This study was a highly collaborative and involved many research groups at the GCI. In particular, Tarek and Sherif worked closely with researchers in the labs of Prof. Peter Siegel and Prof. Morag Park. "This project would not have been possible without the close collaboration with the labs of Dr. Siegel and Dr. Park as well as the invaluable contributions from everyone in the Muller lab. Everyone was instrumental in the success of this project and we are grateful for the tight-knit community at the GCI," expressedTarek.

To learn more, read the publication “The Tumor-Derived Cytokine Chi3l1 Induces Neutrophil Extracellular Traps that Promote T cell Exclusion in Triple Negative Breast Cancerhere.

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